A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

Three different series of cis-restricted analogues combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed between the two aryl rings, were prepared by palladium-mediated coupling approach and evaluated for their antiproliferative activity against six human cancer cell lines. In 1,2-diaryl derivatives, results suggested presence 3?,4?,5?-trimethoxyphenyl moiety at N-1 position ring was more favorable activity. 3,4-diarylpyrrole analogues, three compounds (11i-k) exhibited maximal activity, showing excellent CA-4 resistant HT-29 cells. Inhibition tubulin polymerization selected 1,2 derivatives (9a, 9c, 9o 10a) similar observed with CA-4, while isomeric 3,4-pyrrole 11i-k generally from 1.5- 2-fold active than CA-4. Compounds 11j 11k only showed as inhibitors colchicine binding comparable Compound had biological properties consistent its intracellular target being tubulin. This compound able block cycle in metaphase induce significant apoptosis concentration 25 nM, following mitochondrial pathway, low toxicity normal More importantly, exerted vivo superior CA-4P, significantly reduce tumor growth syngeneic murine model even lower dose tested (5.0 mg/kg).